Correspondence to Gregory J. del Zoppo, MD, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, SBR-17, La Jolla, CA 92037. E-mail grgdlzop{at}riscsm.scripps.edu
Methods—After exclusion of intracranial hemorrhage by CT
scan, patients with abrupt onset of symptoms of focal ischemia
likely to receive treatment within 6 hours who satisfied all clinical
eligibility criteria underwent carotid angiography. Patients displaying
Thrombolysis in Acute Myocardial Infarction grade 0 or 1
occlusion of the M1 or M2 middle cerebral artery were randomized 2:1 to
receive rpro-UK (6 mg) or placebo over 120 minutes into the proximal
thrombus face. All patients received intravenous heparin.
Recanalization efficacy was assessed at the end of
the 2-hour infusion, and intracerebral
hemorrhage causing neurological deterioration was assessed at
24 hours.
Results—Of 105 patients who underwent angiography, 59 were
excluded from randomization. Among the 46 patients randomized, 40 were
treated with rpro-UK (n=26) or placebo (n=14) a median of 5.5 hours
from symptom onset. Recanalization was
significantly associated with rpro-UK (2P=.017).
Hemorrhagic transformation causing neurological deterioration within 24
hours of treatment occurred in 15.4% of the rpro-UK–treated patients
and 7.1% of the placebo-treated patients (2P=.64). Both
recanalization and hemorrhage frequencies
were influenced by heparin dose.
Conclusions—Intra-arterial local rpro-UK infusion was
associated with superior recanalization in acute
thrombotic/thromboembolic stroke compared with placebo. In this
regimen, heparin dose influenced hemorrhage frequency and
recanalization. Although symptomatic
hemorrhage remains a concern, this study suggests that
recanalization is enhanced with rpro-UK and
heparin.
The Prolyse in Acute Cerebral Thromboembolism (PROACT) trial is
the first randomized, double-blind, multicenter trial comparing the
safety, recanalization frequency, and clinical
efficacy of direct intra-arterial infusion of recombinant
pro-urokinase (rpro-UK) with placebo in patients with
symptomatic MCA occlusion of less than 6 hours' duration.
rpro-UK is a relatively thrombus-specific, single-chain proenzyme that
is converted to two-chain urokinase (u-PA) by fibrin-associated plasmin
at the thrombus.10 11 12 13
The objective of this study was to examine the dose-rate response of
directed rpro-UK infusion on recanalization in an
angiographically defined subgroup of acute ischemic stroke
patients with M1 or M2 MCA occlusions. This subgroup of severely
affected patients was expected to have similar clinical
presentations and anticipated outcomes. A placebo group was
included to evaluate safety aspects of the angiographic and
interventional procedures and to provide a basis for assessment of the
contribution of rpro-UK to recanalization (without
mechanical disruption).
The general hypothesis to be tested in this phase II study was that
infusion of rpro-UK within the proximal thrombus face could safely
produce superior recanalization compared with
placebo. Conceived of as a two-part phase II introduction to a larger
phase III comparison of clinical outcome after
intra-arterial delivery of rpro-UK with placebo, we report
here the results of the 6-mg dose tier of the phase II trial.
The clinical inclusion criteria required that patients (1) have a new
onset of focal neurological signs in the MCA distribution allowing
randomization and initiation of treatment within 6 hours of the onset
of symptoms; (2) have a minimum NIHSS14 score of
4, except for isolated aphasia or isolated hemianopsia; and (3) be 18
to 85 years old. Clinical exclusion criteria included an NIHSS score
>30, coma, minor stroke symptoms, or a history of stroke within the
previous 6 weeks; suspected lacunar stroke; seizure at stroke onset;
clinical presentation suggestive of subarachnoid
hemorrhage (even if the initial CT scan was normal); evidence
or history of intracranial hemorrhage at any time or an
intracranial neoplasm; uncompensated hypertension (blood pressure
>180/100 mm Hg); presumed septic embolus or endocarditis;
surgery or trauma (within 30 days); head trauma (within 90 days);
active or recent hemorrhage within 14 days; known hereditary or
acquired hemorrhagic diathesis; or oral anticoagulation with an
international normalized ratio >1.5.
CT scan exclusion criteria were evidence of hemorrhage of any
degree, significant mass effect with midline shift, or the presence of
an intracranial tumor (except a small meningioma). Patients with early
changes of ischemia on CT were included.
Patients who were not excluded by clinical or CT criteria and for whom
informed consent was obtained underwent diagnostic cerebral
angiography of the symptomatic carotid artery territory.
Angiographic inclusion criteria were complete occlusion (TIMI grade
0)15 or contrast penetration with minimal
perfusion (TIMI grade 1) of either the horizontal M1 segment or the M2
division of the MCA. Patients not meeting the angiographic inclusion
criteria were followed for neurological deterioration and/or serious
adverse events for 24 hours or until alternative treatment was
initiated, whichever came first.
If an M1 or M2 occlusion was documented, the patient was allocated by
the Central Randomization Center to receive either 6 mg rpro-UK or
saline placebo at a 30-mL/h controlled infusion rate (tier I). An
infusion microcatheter with a single end hole was placed into the
thrombus extending as far as the proximal third of the thrombus.
Penetration through the clot was proscribed to avoid mechanical
disruption. Local infusion into the M1 segment was permitted when the
microcatheter could not be embedded into the clot. More proximal
regional infusions were prohibited. A second angiogram was performed at
60 minutes. If partial clot lysis had occurred, the catheter was
advanced into the proximal third of the remaining thrombus. The total
amount of rpro-UK or placebo was infused over 2 hours in all patients,
whether or not complete lysis had occurred previously. A final
postinfusion angiogram was then performed through the
diagnostic catheter in the cervical internal carotid
artery.
The primary efficacy outcome was recanalization of
the M1 or M2 MCA at 120 minutes after initiation of infusion. All
angiograms were assessed by the Core
Neuroradiology Facility, which was blinded to
treatment assignment and clinical status. Patients with partial (TIMI
2) or complete (TIMI 3) recanalization were
considered "responders." Complete responders were defined as
patients with TIMI 3 grade patency in all M1 and M2 arteries. The
proportions of patients demonstrating complete, partial, or no
recanalization of all target M1 and M2 occlusions
on the 120-minute diagnostic angiogram were compared
between treatment groups. Clinical outcome was assessed according to
the NIHSS,14 modified Rankin
Scale,16 and Barthel
Index17 at 7 days, 30 days, and 90 days after
treatment. All investigators and examining physicians were blinded to
treatment assignment.
The primary safety outcome was hemorrhagic transformation causing
neurological deterioration within 24 hours of treatment. Established
definitions of hemorrhagic transformation were applied to all CT
scans.1 18 Hemorrhagic infarction was defined as
areas of petechial or confluent petechial hemorrhage within
regions of more homogeneous ischemic injury.
Parenchymatous hematoma formation referred to regions of more
homogeneous high attenuation that contributed to mass
effect or midline shift of cerebral structures or that were associated
with intraventricular extension. Attempts were also
made to distinguish hemorrhage from contrast stain of the
parenchyma by analysis of Hounsfield units on serial scans.
Continuation or termination of the study was dependent on application
of prospectively established limits of hemorrhagic transformation with
deterioration by the External Safety Committee. Those rules stated that
the study would be placed on moratorium if more than nine patients in a
dose tier experienced neurological deterioration caused by any form of
intracranial hemorrhage. Safety was also assessed by comparison
of serious adverse events, other bleeding complications, and changes
from baseline laboratory parameters between treatment
groups.
All patients received intravenous heparin for 4 hours, on
verification of an occluding thrombus. Heparin flush solutions for
angiography contained 1 IU/ml heparin in 0.9% sodium chloride and were
infused at 60 mL/h. The first 16 patients received a 100-IU/kg bolus
followed by a 1000 IU/h constant infusion ("high heparin") for 4
hours. Thereafter, on the recommendation of the External Safety
Committee, the heparin regimen was altered to a 2000 IU bolus and 500
IU/h infusion ("low heparin") for the remaining patients. Oral
anticoagulants were prohibited for 24 hours after completion of
treatment.
For sample size calculations, a spontaneous
recanalization frequency at 2 hours of 20% and an
expected recanalization frequency of 65% in the
rpro-UK group with a 2:1 distribution of rpro-UK to placebo was
assumed. It was estimated that 45 patients (30 in the rpro-UK group and
15 in the placebo group) in each of the two dose tiers (6 mg and 12 mg)
would provide a power of >80% to detect this difference at the
two-sided .05 level.
The trial was halted in February 1995, 1 year after it began, by Abbott
Laboratories near the end of the 60-mg dose tier study to determine
whether there was sufficient evidence of efficacy and safety to support
continuation of a longer-term program. No safety concerns were involved
in that decision. The sponsor agreed to provide a copy of the complete
database to a statistical unit independent of the original conduct of
the study. An independent analysis of the data set from the 105
patients who underwent angiography was performed by the Clinical Trials
Methodology Group at the Hamilton Civic Hospitals Research Center and
is summarized here.
All attributes and outcomes between treatment groups were compared with
the use of Fisher's exact test. All probability values are two
sided.
Of the 105 patients who underwent angiography, 46 patients (43.8%) who
had complete occlusions of the M1 or M2 MCA were randomized. The
remaining 59 patients either had no occlusion within the carotid
territory (n=25) or no M1 or M2 lesions (n=34). Of the 46 randomized
patients, 6 (5 rpro-UK, 1 placebo) did not receive study medication: 2
patients were randomized prematurely and were subsequently found not to
satisfy the angiographic criteria, 2 had postrandomization delays that
placed them beyond the 6-hour time limit, and 2 experienced
complications of the diagnostic angiography (eg, vasospasm
and seizure in separate patients). Those 6 patients were followed
together with the 59 nonrandomized and 40 randomized patients for
safety outcomes. Analysis of the primary
recanalization efficacy outcome was based,
therefore, on the 40 patients who completed treatment and follow-up (26
patients in the rpro-UK group and 14 patients in the placebo
group).
Of the 105 patients, 77 (73.3%) had occlusions in the carotid
territory. The technical feasibility of completing the CT scan studies
(Fig 2
Baseline diagnostic angiography was performed at a median
time of 4.5 hours from symptom onset in 105 patients, and treatment was
initiated in the 40 patients who received study medication at a median
time of 5.5 hours from symptom onset. The rpro-UK and placebo groups
were well matched with regard to median entry NIHSS scores, the
presumed source of occlusion, sex, and age (Table 1
Partial or complete recanalization at 120 minutes
from treatment onset was observed in 15 of 26 patients (57.7%) treated
with rpro-UK compared with 2 of 14 placebo patients (14.3%)
(2P=.017) (Table 2
Early ischemic changes, usually marked by subtle sulcal
effacement or loss of gray-white matter distinction, were observed on
the initial CT scan in 23 of the 40 treated patients (57.5%). Among
those patients, 5 displayed baseline evidence of injury exceeding 33%
of the affected hemisphere on the initial CT scan (ECASS
criteria19 ). All 5 patients with those findings
received rpro-UK and developed hemorrhagic transformation within 24
hours.
Intracerebral hemorrhagic complications are summarized
in Table 3
During the early course of the study the frequency of cerebral
hemorrhage that caused neurological worsening, while not in
excess of the prospectively established stopping limits, was considered
worrisome. The frequency of hemorrhagic transformation within 24 hours
of treatment was 72.7% in the rpro-UK and 20.0% in the placebo groups
exposed to the initial heparin regimen (Table 3
Although the number of patients was too small to establish statistical
significance, there appeared to be a 10% to 12% absolute increase in
excellent neurological outcome in the rpro-UK group over placebo at 90
days (Table 4
Sixteen adverse events occurred in 14 of the 105 patients who underwent
diagnostic angiography. One patient had three events. Three
patients (2.9%) experienced worsening of their clinical condition.
Adverse clinical events following angiography were reported in 5
patients. In 1 patient, transient vasospasm of the catheterized
cavernous internal carotid artery was attributed to the
catheterization, but neurological deterioration was
attributed to the signal stroke. Of the remaining 4 patients, 1
suffered a seizure during the screening angiogram, worsened
neurologically, and ultimately died. A second patient, who also
suffered two injection site hemorrhages, had a 2-point change
in the NIHSS after the 120-minute angiogram. None of these patients
received treatment. Among 2 patients who received rpro-UK, 1 suffered
acute worsening of chronic renal insufficiency due to the radiocontrast
agent. A second patient was unable to handle oral secretions during the
infusion and developed an aspiration pneumonia but subsequently
improved. Injection site hemorrhages occurred in 10 patients,
two of which were severe, justifying transfusion in 1 patient. These
affected 3 patients each who received placebo, rpro-UK, or were not
randomized and 1 patient who did not receive treatment.
Symptomatic intracerebral
hemorrhage within 24 hours was not reported in any of the 65
patients who did not receive study treatment.
To evaluate the contribution of the plasminogen
activator alone to thrombus lysis, mechanical disruption of
the thrombus was proscribed and catheter delivery of the placebo was
used. To limit the exposure of patients to the placebo and still assess
the risks of the delivery system, a 2:1 randomization scheme was
employed. The ethical basis for the use of a placebo in this context
has been described elsewhere.20 This was based
primarily on the desire to evaluate properly the efficacy of
intra-arterial thrombolysis by the
plasminogen activator alone, in which patient
safety was carefully monitored.
rpro-UK is the 411 amino acid single-chain zymogen precursor of u-PA
derived and purified from stably transfected murine SP2/0 hybridoma
cells.11 The zymogen remains inactive in the
absence of fibrin, is not inhibited by circulating
plasminogen activator inhibitors
(eg,
The potential contribution of concomitant heparin therapy to
hemorrhagic transformation was also examined. Although the high-dose
heparin regimen nearly doubled the recanalization
frequency, it was also associated with a substantial increase in
clinically significant brain hemorrhages (Table 3
This study did not exclude patients with early signs of
ischemic injury on the entry CT scan as defined by the ECASS
group.19 Somewhat more than one half of the 40
patients treated had evidence of subtle effacement or loss of
gray-white matter distinction. Of those patients, all five who
displayed evidence of ischemic injury exceeding one third of
the affected hemisphere developed hemorrhage at the
ischemic site within 24 hours after treatment with rpro-UK.
This experience was consistent with that noted in
ECASS.19 There was no difference in the frequency
of hemorrhage with clinical deterioration between the rpro-UK
and placebo groups by the end of this study, however.
Recent trials of intravenous thrombus lysis in acute
ischemic stroke place this impression into perspective. Three
placebo-controlled trials of intravenous streptokinase were
abandoned because of an unacceptably high frequency of hemorrhagic
complications or early mortality.28 29 30 Although
dose rates of streptokinase were not tested before those trials, at
least one was complicated by treatment of patients with extraordinarily
severe neurological deficits.29 The ECASS and the
NINDS intravenous rt-PA trials both included large numbers
of patients selected primarily on the basis of time from symptom onset,
degree of neurological deficit, and CT
criteria.19 31 In ECASS, intravenous
rt-PA (alteplase, 1.1 mg/kg) provided no apparent clinical benefit when
given to patients with evidence of hemispheric injury within 6 hours of
stroke onset limited by CT scan criteria. The study confirmed the
relevance of severe tissue injury on entry CT scan to parenchymal
hematoma formation (19.4%, rt-PA versus 6.8%, placebo) after
treatment with rt-PA. In the NINDS trial, despite an increased
incidence of symptomatic intracerebral
hemorrhage, treatment with rt-PA (0.9 mg/kg, alteplase) within
3 hours of the onset of ischemic stroke resulted in an 11% to
13% absolute increase in full or nearly full recovery at 3 months. In
the present study, patients who received rpro-UK had a
nonsignificantly better neurological outcome at 90 days (Table 4
In nonangiographic trials of plasminogen
activators in acute stroke, it is difficult to assess their
effect in individual patients because ischemic stroke has
diverse etiologies with highly variable natural
histories.32 33 For example, the frequency of
symptomatic parenchymal hematoma formation in the placebo
groups differed markedly between ECASS and the NINDS trial (6.4%
versus 0.6%, respectively), suggesting different patient populations.
The distribution of key variables such as the site of
arterial occlusion and recanalization
efficacy was not determined in those intravenous studies.
In the present study, 73% of patients undergoing angiography had
occlusions in the carotid territory within 6 hours from symptom onset,
confirming previous experience in this
territory.1 34 One angiography-based trial
demonstrated that complete internal carotid artery and M1 MCA
occlusions were significantly less likely to undergo successful
recanalization with intravenous
infusion of rt-PA (duteplase) than peripheral
lesions.1 In the present study, proximal MCA
stem occlusions were chosen to provide a vascular and therefore
neurologically homogeneous subpopulation of smaller size
for study. Ultimately, if recanalization efficacy
could be safely shown in this subpopulation, clinical benefit in a
larger population with distal occlusions would be testable.
Although cumulative experience suggests a much greater
recanalization frequency from direct
intra-arterial infusion than from intravenous
infusion of several plasminogen activators,
neither a pivotal clinical efficacy trial of intra-arterial
thrombolysis nor a direct comparison between
intravenous and intra-arterial
thrombolysis has been completed to
date.20 The intravenous trials
reported thus far do not obviate the direct intra-arterial
delivery approach. Significant improvements in delivery systems since
the earlier reports describing feasibility and safety of the overall
approach, as well as the use of disability measures for clinical
outcome,19 31 35 36 underscore an increased
sophistication in evaluating vascular therapies in stroke patients.
Symptomatic hemorrhagic transformation remains a central
concern, although this study shows that the frequency of such events
can be manipulated by attention to concomitant anticoagulant therapies.
Based on the 65 patients who underwent angiography but were not treated
in this study, the angiographic procedure per se did not contribute to
hemorrhagic transformation. In this regard, one large retrospective
study has indicated that the relative risks of diagnostic
angiography are low.37 38 39 Of the patients
undergoing the interventional procedure in this study, five suffered
adverse clinical events. The relationship of the events to the
procedures, as well as whether the number of events was excessive, must
await evaluation of larger treatment cohorts. Recent insights into the
manner in which the severity of the initial neurological status may
have an impact on hemorrhagic transformation and poor
outcome,19 evidence of
recanalization efficacy demonstrated here, and the
safety of the delivery system support further investigations of the
clinical efficacy and safety of intra-arterial
thrombolysis in acute thrombotic stroke.
An exploratory study is now in progress in which 180 patients with an
acute thrombotic or thromboembolic stroke of the isolated MCA are
randomized in a 2:1 ratio to either intra-arterial rpro-UK
(9 mg) or an intravenous control.
University of Michigan, Ann Arbor, Mich (1/2): Marc I. Chimowitz,
MD (Principal Investigator [PI]); John P. Deveikis, MD; William G.
Barsan, MD; Philip Scott, MD; Zahra Noorani, MBBS
Alta Bates Medical Center, Berkeley, Calif (0/4): Todd E.
Lempert, MD (PI); Anton C. Pogany, MD; Randall R. Starkey, MD; William
Harrington, MD; Erik Gaensler, MD; Robyn G. Young, MD; Barbara A.
McQuinn, MD; Brian C. Richardson, MD; Regis Kwo, MD; Joanna Cooper, MD;
D. Eric Collins, MD; Frank A. Dustin, MD
New England Medical Center, Boston, Mass (1/0): Michael S. Pessin, MD
(PI); Louis R. Caplan, MD; L. Dana DeWitt, MD; John R. Belden, MD;
David G. Mandelkern, MD; Loretta Barron, RN
Millard Fillmore Hospital, Buffalo, NY (2/6). L.N. Hopkins, MD (PI);
Peter Kinkel, MD; Vernice Bates, MD; Aaron Burstein, PharmD; Terry
Fullerton, PharmD; Kenneth Murray, MD; Laszlo Mechtler, MD; James L.
Budney, MD; Kevin Gibbons, MD; Robert Plunkett, MD; Walter Grand, MD;
Eugene J. Gosy, MD; Tamerla Chavis, MD; Lee R. Guterman, MD; William
Kinkel, MD; Fran Gengo, PharmD
Medical University of South Carolina, Charleston, SC: Joseph A. Horton,
MD (PI); Timothy Carter, MD
Rush Presbytarian St Luke's Medical Center, Chicago, Ill: Jeffrey C.
Curtin, DO (PI); Philip B. Gorelick, MD, MPH; Michael A. Kelly, MD;
Jerrold Leikin, MD; Glenn Geremia, MD
Cleveland Clinic Foundation, Cleveland, Ohio (10/4): Anthony J. Furlan,
MD (PI); Cathy A. Sila, MD; Jeffrey Frank, MD; Joseph P. Hanna, MD;
Thomas J. Masaryk, MD; Paul M. Ruggieri, MD; Robert Wallace, MD;
Daryl W. Thompson, MD; John Perl, MD; Brian Dyko, RN
Baylor University Medical Center, Dallas, Tex (0/1): Frank J. Rivera,
MD (PI); Steven P. Herzog, MD; Bruce Jenevein, MD; Alan W. Martin, MD;
Joseph T. Phillips, Jr, MD; Gary L. Tunell, MD
University of Texas Southwestern Medical Center, Dallas, Tex (1/2):
Ralph G. Greenlee, Jr, MD (PI); D. Hal Unwin, MD; Phillip Purdy, MD;
George Carstens III, MD; Rance Boren, MD
Harper Hospital/Detroit Medical Center, Detroit, Mich (1/0): Ramon
Berguer, MD, PhD (PI); Lourdees V. Andaya, MD; Alfredo Lazo, MD; Ralph
Duman, MD; John Kelly, DO; Christopher J. Mehalf, MD; Joseph Metes, MD;
Harvey I. Wilner, MD; Jeffrey M. Wilseck, DO; Mark Friedland, MD;
Steven Koch, PA; Shirley Dixon, MD; Padraic J. Sweeny, MD; Ronald A.
Kline, MD; Brooks F. Bock, MD; Michael W. Kelsher, DO; Nora Bass, BSN,
RN
The Methodist Hospital, Houston, Tex (1/5): Michel E. Mawad, MD (PI);
Richard M. Armstrong, MD; John P. Winikates, MD; Linda Chi, MD; Pedro
Diaz, MD; James Killian, MD
Scripps Clinic and Research Foundation, La Jolla, Calif: Gregory J. del
Zoppo, MD (PI); Shirley M. Otis, MD; Jack Zyroff, MD; David F. Sobel,
MD; Harry J. Knowles, MD; Mohsin Saeed, MD; Peter J. Yang, MD
Lackwood Hospital, Lakewood, Ohio: Arthur P. Dick, MD (PI); Thomas
J. Massaryk, MD; Robert C. Wallace, MD; John Perl II, MD; Darryl
Tompson, MD
University of Wisconsin Hospital and Clinics, Madison, Wis (0/3): Henry
S. Schutta, MD (PI); Charles M. Strother, MD; Brad R. Beinlich, MD;
Virgil B. Graves, MD; Steven R. Hughes, MD; Ross L. Levine, MD; Douglas
A. Dulli, MD; Andrew J. Waclawik, MD; Barend P. Lotz, MB, ChB
Yale University, New Haven, Conn (4/1): Pierre B. Fayad, MD (PI);
Lawrence M. Brass, MD; John Christopher Chaloupka, MD; Dana Leifer, MD;
Michael Joel Schneck, MD; Harry Moscovitz, MD; Kimberly A. Pace
Columbia Presbyterian NY, New York, NY: John Pile-Spellman, MD (PI);
J.P. Mohr, MD; H. Mast, MD; L. Hacein-Bey, MD; J. Demerrit, MD; W.
Young, MD
New York University Medical Center, New York, NY: David N. Levine, MD
(PI); Alejandro Berenstein, MD; Keith Siller, MD; Avi Setton, MD; Peter
Kim Nelson, MD
University of Pittsburgh Medical Center, Pittsburgh, Pa (4/10):
Lawrence R. Wechsler, MD (PI); Charles Jungreis, MD; Laurie Knepper,
MD; Benjamin Eldelman, MD; Howard Yonas, MD; W. Andrew Kofke, MD; Kevin
O'Toole, MD; Anthony Kaufmann, MD; Benjamin Shtrahman, MD
Oregon Health Sciences University, Portland, Ore (2/7): Wayne M. Clark,
MD (PI); Stanley L. Barnwell, MD, PhD; Bruce M. Coull, MD; Michael
Wynn, DO; Gary M. Nesbit, MD
Lewis-Gale Clinic, Inc, Salem, Va (0/2): Timothy L. Hormel, MD (PI);
Edward A. Waybright, MD; Howard B. Sherman, MD; Mary E. Jensen, MD;
Jacques E. Dion, MD
University of Utah Hospital, Salt Lake City, Utah (6/5): John Jacobs,
MD (PI); Gregory Call, MD; John F. Foley, MD
University of California San Francisco Medical Center, San Francisco,
Calif (1/0): Randall T. Higashida, MD (PI); Grant B. Hieshima, MD; Van
V. Halbach, MD; Christopher F. Dowd, MD; Daryl R. Gress, MD; Claude
Hemphill, MD; Wade S. Smith, MD
St Louis University Health Sciences Center, St Louis, Mo (1/1): Camilo
R. Gomez, MD (PI); Marc D. Malkoff, MD; Christina M. Burch, MD; Eric
Awwad, MD; David S. Martin, MD
Scott and White Hospital, Temple, Tex (1/0): J. Hise, MD (PI); A.
Follender, MD; J. Wilkinson, MD; R. Lenehan, MD; D. Keyser, MD; D.
Crisp, MD; J. Clark, MD; R. Calvo, MD; G. Shultz, MD; Pat Kirkpatrick,
RN
Toronto Western Division Hospital, Toronto, Canada
(5/2): Frank L. Silver, MD (PI); Karel G. TerBrugge, MD; Walter
Montanera, MD; Robert A. Willinsky, MD; Catherine A. Zahn, MD
Vancouver General Hospital, Vancouver, British Columbia, Canada (5/3):
Philip Teal, MD (PI); Jocelyne S. Lapointe, MD; Robert A. Nugent MD;
Douglas A. Graeb, MD; Tom Marotta, MD; Michelle M. Mezel, MD; Andrew R.
Woolfenden, MD; Brian Thiessen, MD
The Bowman Gray School of Medicine, Winston-Salem, NC (0/1): Don
Antonio Bell, MD (PI); Steven Glazier, MD; John Wilson, MD; James
Toole, MD
Executive and Steering Committees: Gregory J. del Zoppo, MD (Chairman),
The Scripps Research Institute; Randall T. Higashida, MD (Co-chairman),
University of California San Francisco; Anthony J. Furlan, MD, The
Cleveland Clinic Foundation; Michael S. Pessin, MD, New England Medical
Center; Michael Gent, DSc, Hamilton Civic Hospitals Research Center;
Martin A. Samuels, MD, Brigham and Women's Hospital; and Charles
Strother, MD, University of Wisconsin Medical Center
Safety Committee: Carlos Kase, MD (Chairman), Boston University School
of Medicine; H.J.M. Barnett, MD, John P. Robarts Research Institute;
and G.F. Molinari, MD, George Washington University
Core Neuroradiology Facility: William P.
Dillon, MD; Howard A. Rowley, MD; and Nancy J. Fischbein, MD,
University of California at San Francisco
Core Coagulation Laboratory: Victor J. Marder, MD, University of
Rochester Medical Center
Liaisons for the Sponsor: Arthur A. Sasahara, MD, and Janet M. Sweeney,
RPh
Abbott Laboratories (Abbott Park, Ill) is the sponsor of the trial reported in this article. Howard A. Rowley, MD, has been a paid consultant to Abbott Laboratories over the past 2 years. The Neuroradiology section at University of California at San Francisco also has a research contract with Abbott Laboratories to provide readings of cases in their ongoing thrombolysis trials; however, Dr Rowley is not directly paid through this activity.
Received May 8, 1997;
revision received October 15, 1997;
accepted October 15, 1997.
© 1998 American Heart Association, Inc.
Original Contributions
PROACT: A Phase II Randomized Trial of Recombinant Pro-Urokinase by Direct Arterial Delivery in Acute Middle Cerebral Artery Stroke
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
Background and Purpose—To test the
safety and recanalization efficacy of
intra-arterial local delivery of plasminogen
activators in acute ischemic stroke, a randomized
trial of recombinant pro-urokinase (rpro-UK) versus placebo was
undertaken in patients with angiographically documented proximal middle
cerebral artery occlusion.
Key Words: stroke, acute • angiography • hemorrhage • pro-urokinase • recanalization
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
There has been a
resurgence of interest in the notion that
recanalization of recently occluded main stem
cerebral arteries by plasminogen activators in
the early moments of acute stroke may lead to efficient neurological
recovery. The feasibility and safety of cerebral arterial
recanalization have been demonstrated in a series
of prospective angiography-based trials of intravenous
infusion of rt-PA (duteplase).1 2 3 Recently,
intravenous rt-PA (alteplase) has been shown to improve
four measures of clinical outcome at 90 days when treatment was
initiated within 3 hours of stroke onset.4
Reported experience using intra-arterial infusion of
fibrinolytic agents in a limited number of patients with complete
carotid territory5 6 or
vertebrobasilar6 7 8 arterial
occlusion suggests that direct intra-thrombus delivery of
plasminogen activators within 6 hours of stroke
onset can recanalize a greater proportion of major
symptomatic cerebral arterial occlusions than
intravenous delivery.9 The
possibility that intra-arterial delivery of a
plasminogen activator with early cerebral
arterial recanalization may lead to
improvement in clinical outcome has not been tested prospectively.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
Between February 1994 and February 1995, 37 North American
clinical centers screened patients with symptoms of acute carotid
artery territory stroke for entry into this study ("Appendix").
Patients who fulfilled all inclusion criteria and failed no exclusion
criteria were randomized in a ratio of 2:1 to receive either rpro-UK or
placebo by intra-arterial infusion. Two rpro-UK doses were
to be evaluated. A 6-mg tier (I) was to be completed before the 12-mg
tier (II) would be initiated.
Results
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Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
During the study 1314 patients were screened for entry, of whom
105 (8.0%) satisfied all clinical and CT scan entry criteria and
underwent baseline diagnostic angiography (Fig 1
). Of the 1209 patients excluded, 387
patients (32.0%) arrived at the hospital too late to start treatment
within 6 hours from stroke onset, an additional 179 (14.8%) had an
NIHSS score <4, 73 (6.0%) had advanced age, and 447 (37.0%) were
excluded for other reasons. An additional 123 (10.2%) patients were
excluded by CT scan criteria.
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Figure 1. Distribution of patients screened for entry and
randomization. 
(T-0) indicates time from symptom onset to
treatment.), the catheter manipulations, and
the directed infusion (Fig 3) was
demonstrated in each of those patients.
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Figure 2. Noncontrast CT scans at baseline (A) and 8 days
after presentation (B) in a 70-year-old man with acute
right hemiparesis and aphasia who underwent angiography 3.4 hours after
symptom onset. A, An old right putamen lacune is evident, but the left
hemisphere appears normal. Subtle evidence of edema can be appreciated
in the left lentiform nucleus. B, There is a new left lentiform nucleus
infarction, but the remainder of the MCA territory appears
normal.
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Figure 3. Serial angiograms (frontal views) at baseline (A),
baseline with initial catheter placement (B), 60 minutes after infusion
(C), and 120 minutes after infusion (D) of rpro-UK in the patient
described in Fig 2 
. A, Left ICA angiogram at baseline. There is an
occlusion of the midportion of the left MCA, just beyond the anterior
temporal branch. B, Microcatheter placement at baseline. The tip of the
catheter (arrow) has been directed into the face of the clot. During
hand injection, contrast outlines a large thrombus filling the distal
M1 segment and origins of the M2 (hemispheric) branches. C,
Microcatheter injection 60 minutes after rpro-UK infusion. The tip of
the catheter (arrow) remains in a similar location. Partial lysis is
demonstrated compared with baseline. D, Left ICA angiogram at 2 hours
after rpro-UK infusion. Note complete lysis and normal-appearing
vascular segments distal to the M1 and M2 MCA.).
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Table 1. Characteristics of Treated Patients ). Five of
the rpro-UK–treated patients displayed complete
recanalization (TIMI grade 3 in all vessels), while
none of the placebo patients achieved a complete response (Fig 3).
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Table 2. Recanalization vs Heparin Dose . Hemorrhagic transformation
within 24 hours of treatment occurred in 11 patients (42.3%) in the
rpro-UK group compared with 1 patient (7.1%) in the placebo group
(2P=.030) (Table 3). Among the rpro-UK patients, 9 displayed
hemorrhagic infarctions (among whom 1 patient displayed
ventricular extension), 1 patient had a parenchymatous
hematoma, and 1 patient had both a hemorrhagic infarction and a
parenchymatous hematoma, as did the single placebo patient. Three
patients had evidence of contrast extravasation and hemorrhagic
infarction. Hemorrhagic transformation causing neurological
deterioration within 24 hours of treatment occurred in 4 (15.4%) of
the rpro-UK-treated patients and 1 placebo-treated patient (7.1%)
(2P=.64). Hemorrhage causing clinical deterioration
at any time within the study period occurred in 4 patients (15.4%) who
received rpro-UK and 2 patients (14.3%) in the placebo group
(2P=1.00). One patient in each treatment group suffered a
fatal intracerebral hemorrhage. Overall, within
the study period there was no significant difference in the frequency
of intracerebral hemorrhage between the rpro-UK
(13; 50.0%) and placebo (5; 35.7%) groups (2P=.51).
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Table 3. Intracranial Hemorrhage ). A recommendation by
the External Safety Committee that the heparin dose be decreased was
accepted, following which the frequency of brain hemorrhage at
24 hours fell to 20% (3 patients) in the rpro-UK group and 0% in the
placebo group (Table 3). Among patients treated with rpro-UK the
frequency of recanalization was 81.8% for the
"high-heparin" group and 40.0% for the "low-heparin" group
(2P=.051). ). Overall, 6 angiographic
responders (35.3%) had a modified Rankin score of 0 or 1 at 90-day
follow-up compared with 5 nonresponders (21.7%) (2P=.48).
The 90-day cumulative mortality was 26.9% in the rpro-UK group and
42.9% in the placebo group (2P=.48). Death was attributed
to medical complications accompanying the initial stroke in 7 patients,
while 4 deaths were due to cardiac causes (Table 5).
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Table 4. Clinical Outcomes at 90 Days
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Table 5. Mortality Within 90 Days
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
This trial is the first double-blinded, randomized,
placebo-controlled study of a plasminogen
activator delivered intra-arterially by
microcatheter in acute thrombotic stroke. The frequency of
recanalization of documented M1 or M2 MCA
occlusions in patients receiving direct intra-arterial
rpro-UK within 6 hours of stroke onset was greater than with placebo,
when the use of heparin was not considered.
Recanalization could not be ascribed to mechanical
disruption of the thrombus. There was no significant difference in
frequency of cerebral hemorrhage causing neurological
deterioration between the rpro-UK and placebo groups at 24 hours or 90
days. However, a contribution of adjunctive intravenous
heparin, accompanying the arteriographic and delivery procedures, to
the frequency of all intracerebral hemorrhages
and to recanalization seemed likely, as suggested
by the respective reductions in both events when the heparin dose was
reduced. However, no relationship between
recanalization and intracerebral
hemorrhage was demonstrable in post hoc analyses, owing
to the small number of patients. 
2-antiplasmin,
2-macroglobulin), and is not activated
in plasma. pro-UK (single chain urokinase plasminogen activator, or
scu-PA) is converted to two-chain u-PA by plasmin and thereby amplifies
plasminogen activation.21 The
implication, confirmed by experimental
work,22 23 24 is that rpro-UK is activated
at the thrombus surface by plasmin associated with the fibrin network,
in a surface-controlled process.25 The
thrombolytic potential remains confined to the thrombus
but is apparently augmented by the concomitant use of
heparin.21 26 In a canine femoral artery
thrombosis model, rpro-UK plus heparin produced a significant increase
in thrombus lysis compared with rpro-UK, vehicle plus heparin, and
vehicle alone26 and minimized further thrombus
accretion. Other experimental data suggest that heparin doses
sufficient to increase the activated partial thromboplastin
time by 1.5 times control markedly increase the
recanalization efficacy of
rpro-UK.27 The combination of rpro-UK and heparin
would therefore be expected to enhance thrombus lysis by direct
intra-arterial infusion. The enhanced thrombus dissolution
and overall benefit in recanalization compared with
placebo seen in this study was dependent on the effect of the higher
heparin dose together with the fixed rpro-UK dose. ). However, no
significant relationship between recanalization and
hemorrhage was seen by post hoc analyses. Limited
experience at the time of study termination suggested that the lower
heparin dose regimen might decrease both
recanalization frequency and hemorrhage
risk. ),
although the study was not powered to test this relationship.
Selected Abbreviations and Acronyms
ECASS
=
European Cooperative Acute Stroke Study
MCA
=
middle cerebral artery
NIHSS
=
National Institutes of Health Stroke Scale
PROACT
=
Prolyse in Acute Cerebral Thromboembolism
NINDS
=
National Institute of Neurological Disorders and Stroke
rpro-UK
=
recombinant pro-urokinase
rt-PA
=
recombinant tissue plasminogen activator
TIMI
=
Thrombolysis in Acute Myocardial Infarction
u-PA
=
urokinase plasminogen activator
Appendix 1
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
PROACT Investigators
Numbers in parentheses indicate the number of group 1 and group
3 patients enrolled, respectively.
Acknowledgments
We wish to thank Marcia Filbert for her expert assistance in the
preparation of this manuscript.
Footnotes
From the Department of Molecular and Experimental Medicine, The Scripps Research Institute and Division of Hematology and Medical Oncology, Scripps Clinic and Research Foundation, La Jolla, Calif (G. del Z.); Departments of Radiology and Neurosurgery, Division of Interventional Neurovascular Radiology (R.T.H.), and Departments of Radiology and Neurology, Division of Diagnostic Neuroradiology (H.A.R.), University of California at San Francisco, UCSF Medical Center; Department of Neurology, The Cleveland Clinic Foundation (Ohio) (A.J.F.); Department of Neurology, Tufts–New England Medical Center, Boston, Mass (M.S.P.); and Hamilton Civic Hospitals Research Center, McMaster University, Hamilton, Ontario, Canada (M.G.).
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
Appendix 1
References
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